Heterocycles are an important structural motif found in the majority of pharmaceuticals and natural products. The Prins cyclisation reaction is one of many methods to prepare these compounds, being demonstrated to have a wide range of applications in pharmaceutical and natural product synthesis. However, the reaction mechanism is still highly disputed, with three predominating approaches in the literature – direct cyclisation (Dobbs), aldehyde incorporation (Maseras) and allyl-transfer (Willis). Our work has examined these three mechanisms comparatively using a mixture of computational and experimental chemistry methods in order to: a) to elucidate the reactive intermediates along each pathway. b) gain an insight into which mechanism(s) are operating under which reaction conditions Based on the known Prins reaction between phenylacetaldehyde and 4-penten-2-ol, computational studies of the direct cyclisation route have been carried out for the first time to determine a full reaction mechanism. In summary, this goes via a key oxocarbenium ion intermediate, with the full reaction pathway possessing 6 reactive intermediates and 2 transition states whereby the Lewis acid is intimately involved throughout. The reaction is shown to be favourable overall by 8.7 kcal/mol. Our work then examines the other two proposed mechanisms. Allyl-transfer is shown to be a competing route with direct cyclisation, sharing the same key oxocarbenium ion intermediate but possessing high energy, homoallylic carbocationic species. Aldehyde incorporation has then been conclusively investigated using an 18-oxygen labelling study. In addition, we have carried out the first mechanistic study of the related silyl-Prins reaction, in particular examining the influence of the silicon group(s) and their resulting effect on the dihydropyran products formed.

Probing the mechanism of the Prins and related reactions via a combined experimental and computational study

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.